Novel heterozygous STUB1 gene mutation causes SCA48 in a Hungarian patient

• Published in: Ideggyógyászati szemle Vol. 76; no. 1-2; p. 63
• Main Authors: Klivényi, Péter, Szpisjak, László, Salamon, András, Németh, Viola Luca, Szépfalusi, Noémi, Maróti, Zoltán, Kalmár, Tibor, Zimmermann, Aliz, Zádori, Dénes
• Format: Journal Article
• Language: English
• Published: Hungary 30-01-2023
• Subjects: Ataxia - diagnosis; Ataxia - genetics; Atrophy; Brain Diseases; Dysarthria; Humans; Hungary; Mutation; Ubiquitin-Protein Ligases - genetics; Hungary; STUB1; hereditary; SCA48; spinocerebellar ataxia; SCAR16
• ISSN: 0019-1442
• DOI: 10.18071/isz.76.0063

Autosomal dominant cerebellar ataxias (ADCA), also known as spinocerebellar ataxias (SCA) are a group of progressive neurodegenerative diseases with remarkable clinical and genetic heterogeneity. In the last ten years 20 genes were identified in the background of SCAs. One of these genes was STUB1 (STIP1 homology and U-box containing protein 1) (chromosome 16p13, NM_005861.4) encoding a multifunctional E3 ubiquitine ligase (CHIP)1. In 2013, STUB1 was identified as a causative gene of autosomal recessive spinocerebellar ataxia 16 (SCAR16), but in 2018 Genis et al. published that heterozygous mutations of this gene can cause the autosomal dominantly inherited SCA48 as well1,2. 28 French, twelve Italian, three Belgian, two North-American, one Spanish, one Turkish, one Dutch, one German and one British SCA48 families have been reported so far2-9. Based on these publications, SCA48 is a late-onset, progressive disorder characterized by cerebellar dysfunction, cognitive impairment, psychiatric features, dysphagia, hyperreflexia, urinary tract symptoms and movement disorders including Parkinsonism, chorea, dystonia and rarely tremor. The brain MRI in all SCA48 patients demonstrated vermian and hemispheric cerebellar atrophy which was more pronounced in the posterior areas (lobules VI and VII) of the cerebellum in most of the cases2-9. Besides this, T2- weighted imaging (T2WI) hyperintensity of dentate nuclei (DN) was reported in some Italian patients10. Moreover, the most recent publication described alterations on DAT-scan imaging in some French families9. Neurophysiological examinations did not find any central or peripheral nervous system abnormalities2,3,5. Neuropathologic findings revealed definite cerebellar atrophy and cortical shrinkage with variable severity6,7. The histopathological assessment denoted Purkinje cell loss, p62-positive neuronal intranuclear inclusions in some cases and tau pathology in one patient6-7.
In this paper we describe the clinical and genetic characterization of the first Hungarian SCA48 case with a novel heterozygous STUB1 gene missense mutation.